KR20230162231A - Methods for preparing 2′,4′,6′-trihydroxyacetophenone monohydrate and 2′,4′,6′-trihydroxyacetophenone monohydrate prepared thereby - Google Patents

Abstract

The present invention relates to a method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate and the 2', 4', 6'-trihydroxyacetophenone monohydrate prepared thereby, and more specifically, to A manufacturing method for obtaining 2', 4', 6'-trihydroxyacetophenone monohydrate in high yield by reducing the production of side reactants that are difficult to separate due to structural similarity, and 2', which is used for lowering cholesterol, prepared thereby. It relates to 4′, 6′-trihydroxyacetophenone monohydrate.

Description

Method for producing 2′, 4′, 6′-trihydroxyacetophenone monohydrate and 2′, 4′, 6′-trihydroxyacetophenone monohydrate produced thereby {METHODS FOR PREPARING 2′,4′, 6′-TRIHYDROXYACETOPHENONE MONOHYDRATE AND 2′,4′,6′-TRIHYDROXYACETOPHENONE MONOHYDRATE PREPARED THEREBY}

The present invention relates to a method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate and the 2', 4', 6'-trihydroxyacetophenone monohydrate prepared thereby, and more specifically, to A manufacturing method for obtaining 2', 4', 6'-trihydroxyacetophenone monohydrate in high yield by reducing the production of side reactants that are difficult to separate due to structural similarity, and 2', which is used for lowering cholesterol, prepared thereby. It relates to 4′, 6′-trihydroxyacetophenone monohydrate.

The present invention provides 2′, 4′, 6′-trihydroxyacetophenone monohydrate, which is known to have the effect of reducing blood cholesterol concentration by increasing the activity of CYP7A1 (Cholesterol 7 alpha-hydroxylase) liver enzyme, which converts cholesterol into bile acid. We seek to develop an effective manufacturing method. When the starting material benzene-1,3,5-triol (phloroglucinol) is acylated, a side reactant with multiple acetyl groups is present, which is 2′, 4′, 6′-trihydroxyacetope. It is structurally very similar to rice paddies, so it is difficult to separate them. There is no related technical literature on synthesizing under conditions that minimize the production of side reactants, efficiently separating the generated side reactants, and simultaneously producing them as monohydrate, so technology for this is needed. Regarding the method for synthesizing 2′, 4′, 6′-trihydroxyacetophenone, the US2010034020 patent (Patent Document 1) recommends reacting with hydrochloric acid gas at a low reaction temperature (-20°C or lower) or prior art documents (Molecules 2014, 19,11645-1165) is a similar product, but the yield is low and it is purified by column chromatography. This is unsuitable and may cause problems during mass reactions, so a method for producing 2′, 4′, 6′-trihydroxyacetophenone monohydrate with higher yield and more efficient than this is needed.

US Patent Publication No. 2010-034020

Based on previous research, the present invention synthesizes 2', 4', and 6'-trihydroxyacetophenone under reaction conditions that can reduce the production of side reactants and separates side reactants that are structurally similar and difficult to purify. Provides a new purification method. Specifically, the conventional manufacturing method generates a large amount of side reactants that are difficult to separate, resulting in low yield and an ineffective purification process. The present invention uses reactants different from conventional production methods to minimize side reactants generated during the production of 2', 4', and 6'-trihydroxyacetophenone. A method is provided to produce 2', 4', 6'-trihydroxyacetophenone monohydrate with a purity of 99.5% or more by separating the generated side reactants using a more efficient purification method than column chromatography.

According to the present invention, preparing a mixture by reacting a first reactant containing benzene-1,3,5-triol (phloroglucinol) with a second reactant containing an acylation material (S1); Creating an aqueous layer-organic layer mixture by adding purified water to the mixture and stirring it (S2); Separating the organic layer of the aqueous layer-organic layer mixture, washing and concentrating the organic layer to obtain a crystalline intermediate product (S3); Mixing the intermediate product with an alcohol mixed solvent to prepare an alcohol mixture (S4); Preparing a final mixture by adding and mixing purified water to the alcohol mixture (S5); Obtaining a recrystallized product by recrystallizing the final mixture (S6); and washing and filtering the recrystallized product (S7); It provides a method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate, characterized in that the acylation material in step (S1) is acetyl chloride.

In step (S1), the first reactant may include benzene-1,3,5-triol (phloroglucinol) and a first organic solvent.

The first organic solvent may include any one of dichloromethane, acetonitrile, and acetic acid.

In step (S1), the second reactant may further include a second organic solvent including any one of dichloromethane, acetonitrile, and acetic acid, and a catalyst.

After adding the second reactant to the first reactant in step (S1), the mixture can be prepared by stirring for 10 to 60 minutes.

The molar ratio of benzene-1,3,5-triol (phloroglucinol) and the acylation material may be 1:1 to 1:2.

The catalyst may include any one of aluminum chloride and boron trifluoride diethyl ether.

The first organic solvent and the second organic solvent may each include dichloromethane, the catalyst may include aluminum chloride, and the acylation material may include acetyl chloride.

In step (S2), the water layer-organic layer mixture may be produced by stirring at a temperature of 0 degrees to 5 degrees.

In step S2, the purified water is added in a state solidified as ice, and can be stirred until the solidified purified water melts.

In step S4, the intermediate product and the alcohol mixed solvent may be mixed by raising the temperature to 50 to 70 degrees Celsius.

In step S5, the volume ratio of the alcohol mixed solvent and purified water may be 1:3 to 1:5.

In step S6, the final mixture may be cooled to 0 to 5 degrees Celsius and recrystallized.

The steps (S4) to (S7) may be repeated 2 to 4 times in order.

According to the present invention, 2', 4', 6'-trihydroxyacetophenone monohydrate is provided, which is prepared by the above production method and is used for cholesterol lowering purposes.

The present invention can increase yield by minimizing the production of side reactants, purify using ethanol and purified water as purification solvents, and produce the target compound, 2′, 4′, 6′-trihydroxyacetophenone monohydrate. There is an advantage in that it can be done. In addition, side reactants that are difficult to separate due to structural similarity can be purified by recrystallization rather than column chromatography to obtain high purity 2', 4', 6'-trihydroxyacetophenone monohydrate in a simple process.

Figure 1 shows a flow chart of the production process of 2', 4', 6'-trihydroxyacetophenone monohydrate of the present invention.

The terms used in this specification and patent claims should not be construed as limited to their ordinary or dictionary meanings, and the inventor may appropriately define the concept of the term in order to explain his or her invention in the best way. It must be interpreted based on principles and with a meaning and concept consistent with the technical idea of the invention. Therefore, the configurations such as the examples described in this specification are only one of the most preferred embodiments of the present invention and do not represent the entire technical idea of the present invention, and various equivalents and It should be understood that there may be variations.

The term “crude 2′, 4′, 6′-trihydroxyacetophenone” used throughout the specification of this application refers to 2′, 4′, As a 6'-trihydroxyacetophenone material, it corresponds to an intermediate produced in a series of intermediate steps in the process for producing 2', 4', and 6'-trihydroxyacetophenone monohydrate.

The terms “about,” “substantially,” and the like used throughout the specification herein are used to mean at or close to the numerical value when manufacturing and material tolerances inherent in the stated meaning are presented, and are used accurately to aid understanding of the present application. It is used to prevent unscrupulous infringers from unfairly exploiting disclosures where absolute figures are mentioned.

Throughout this specification, the term "combination(s) thereof" included in the Markushi format expression means one or more mixtures or combinations selected from the group consisting of the constituent elements described in the Markushi format expression, It means including one or more selected from the group consisting of the above components.

Throughout this specification, the description of “A or B” means “A or B or both.”

Method for producing 2’, 4’, 6’-trihydroxyacetophenone monohydrate and 2’, 4’, 6’-trihydroxyacetophenone monohydrate prepared thereby

The present invention relates to a method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate and 2', 4', 6'-trihydroxyacetophenone monohydrate prepared thereby. More specifically, the method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate of the present invention includes a mixture preparation step (s1), an aqueous layer-organic layer mixture preparation step (S2), an intermediate product preparation step (S3), It is characterized by comprising an alcohol mixture preparation step (S4), a final mixture preparation step (S5), a recrystallization product preparation step (S6), and a washing and filtration step (S7).

Figure 1 is a flow chart briefly dividing the manufacturing process of the 2', 4', and 6'-trihydroxyacetophenone monohydrate into stages. Referring to Figure 1, the 2', 4', and 6' of the present invention. -The manufacturing method of trihydroxyacetophenone monohydrate is explained step by step.

Mixture preparation step (S1)

This is a step of preparing a mixture by reacting a first reactant containing benzene-1,3,5-triol (phloroglucinol) with a second reactant containing an acylation material.

The first reactant specifically includes benzene-1,3,5-triol (phloroglucinol) and a first organic solvent, and more specifically, the first organic solvent is any one of dichloromethane, acetonitrile, and acetic acid. Includes one.

The benzene-1,3,5-triol (phloroglucinol) is included in an amount of 5 to 15 parts by weight based on 100 parts by weight of the first organic solvent.

The second reactant specifically includes an acylation material, a second organic solvent, and a catalyst.

The second reactant is preferably prepared by first mixing and stirring the second organic solvent and catalyst, and then adding the acylation material 2 to 30 times for 5 to 30 minutes.

The second organic solvent includes any one of dichloromethane, acetonitrile, and acetic acid.

The acylation material serves to replace some of the hydrogen atoms included in the molecular structure of benzene-1,3,5-triol (phloroglucinol) contained in the first reactant with an acyl group.

The acylation material preferably contains acetyl chloride.

The molar ratio of the benzene-1,3,5-triol (phloroglucinol) and the acylation material is 1:0.6 to 1:1.9, preferably 1:0.8 to 1:1.5. More preferably, it may be 1:1 to 1:1.1.

The acylation material is included in an amount of 5 to 15 parts by weight based on 100 parts by weight of the second organic solvent.

The catalyst may include either aluminum chloride or boron trifluoride diethyl ether, and more preferably, the catalyst may be aluminum chloride.

The catalyst is included in an amount of 10 to 25 parts by weight based on 100 parts by weight of the second organic solvent.

After adding the second reactant to the first reactant and reacting it, the mixture is prepared by stirring for 10 to 60 minutes. At this time, the reaction of the first reactant and the second reactant is preferably carried out at 25 to 30 degrees Celsius under nitrogen conditions.

Water layer-organic layer mixture preparation step (S2)

This is the step of adding purified water to the mixture and stirring it to create an aqueous layer-organic layer mixture.

The aqueous layer-organic layer mixture has the property of being separated into an aqueous layer and an organic layer. Water-soluble substances are dissolved in the aqueous layer, and fat-soluble substances are dissolved in the organic layer.

The aqueous layer-organic layer mixture is preferably prepared by stirring at a temperature of 0 to 5 degrees Celsius.

The purified water may be added in a state solidified as ice, and stirred until the solidified purified water melts to prepare an aqueous layer-organic layer mixture separated into an aqueous layer and an organic layer.

Intermediate product manufacturing step (S3)

This is the step of separating the organic layer from the aqueous layer-organic layer mixture, washing and concentrating the organic layer to obtain a crystalline intermediate product.

The aqueous layer can be extracted by adding dichloromethane, and then the organic layer can be collected and washed using 2M to 3M hydrochloric acid (HCl).

Additionally, the organic layer can be further washed with sodium bicarbonate solution or saturated salt water and dehydrated with anhydrous sodium sulfate to obtain an intermediate product with almost no impurities removed.

Alcohol mixture preparation step (S4)

This is a step of preparing an alcohol mixture by mixing the intermediate product with an alcohol mixed solvent.

The alcohol mixed solvent is any one selected from the group consisting of methanol, ethanol, isopropyl alcohol, and combinations thereof, or a solvent mixed with water and any one selected from the group consisting of methanol, ethanol, isopropyl alcohol, and combinations thereof. It can be done daily.

It is preferable that the intermediate product and the alcohol mixed solvent are mixed at a temperature of 50 to 70 degrees Celsius.

Final mixture preparation step (S5)

This is the step of preparing the final mixture by adding and mixing purified water to the alcohol mixture.

The purified water can be slowly added over 30 to 60 minutes in a temperature environment of 55 to 60 degrees Celsius.

The volume ratio of the alcohol mixed solvent and purified water is preferably 1:3 to 1:5.

Recrystallization product preparation step (S6)

This is the step of recrystallizing the final mixture to obtain a recrystallization product.

The recrystallization is preferably performed in a lower temperature environment than the step of preparing the final mixture (S5). Specifically, the final mixture may be cooled to 0 to 5 degrees Celsius to allow recrystallization to proceed.

Washing and filtration step (S7)

This is a step of washing and filtering the recrystallized product.

The recrystallized product can be washed with purified water or the like and then filtered.

The alcohol mixture preparation step (S4), the final mixture preparation step (S5), the recrystallization product preparation step (S6), and the washing and filtration step (S7) can be performed repeatedly, and as the steps are repeated, the production yield will improve. You can. Preferably, the steps (S5) to (S7) are repeated 2 to 4 times in order, and the finally filtered product is dried to obtain 2', 4', 6'-trihydroxyacetophenone monohydrate. can do.

2', 4', 6'-trihydroxyacetophenone monohydrate obtained by the above production method is characterized by having a purity of 99.5% or more, and 2', 4', 6'-trihydroxyaceto of the above purity Phenone monohydrate can be used to lower cholesterol.

Hereinafter, the present invention will be described in more detail through specific examples and comparative examples.

Example 1

에서 10분간 교반하고, 상기 반응혼합물에 아세틸 클로라이드 11.4mL(158mmol)를 10분간 투입하여 제조된 제2 반응물을 혼합하여 20~25

온도환경에서 1시간 동안 교반하여 혼합물을 제조하였다. 이후 상기 혼합물에 얼음을 투입하여 반응을 종결시키고 10분간 교반하여 수층 및 유기층으로 층분리된 수층-유기층 혼합물을 제조하였다. 상기 수층에 디클로로메탄을 가하여 추출한 다음, 상기 유기층을 모아 3M의 HCl로 세척하였다. 상기 유기층에 탄산수소나트륨 포화수용액 및 포화소금물로 번갈아 세척한 후, 무수황산나트륨으로 탈수처리하여 중간 생성물인 크루드(crude) 2, 4, 6-트리히드록시아세토페논 결정을 수득하였다.100 mL of dichloromethane was added to the first reactant, which was a mixture of 20 g (158 mmol) of benzene-1, 3, 5-triol (phloroglucinol) and 160 mL of dichloromethane, and 23.3 g (174 mmol) of aluminum chloride.

was stirred for 10 minutes, and the second reactant prepared by adding 11.4 mL (158 mmol) of acetyl chloride to the reaction mixture for 10 minutes was mixed and mixed for 20 to 25 minutes.

The mixture was prepared by stirring for 1 hour in a temperature environment. Afterwards, ice was added to the mixture to terminate the reaction, and the mixture was stirred for 10 minutes to prepare an aqueous layer-organic layer mixture separated into an aqueous layer and an organic layer. Dichloromethane was added to the aqueous layer for extraction, and then the organic layer was collected and washed with 3M HCl. The organic layer was washed alternately with a saturated aqueous solution of sodium bicarbonate and saturated salt water, and then dehydrated with anhydrous sodium sulfate to obtain crude 2, 4, 6-trihydroxyacetophenone crystals as an intermediate product.

로 승온하여 용해시켰다. 이후, 정제수 120mL를 약 1시간 동안 천천히 나누어 투입 및 혼합하여 최종 혼합물을 제조하였다. 상기 최종 혼합물을 약 0~5

로 냉각하여 재결정 생성물을 얻었다. 이후 상기 재결정 생성물을 여과하고 정제수로 세척하였다. 이후 상기 에탄올을 투입하고 재결정 생성물을 여과하기까지의 과정을 2차례 반복 실시한 후, 이를 건조하여 2', 4', 6'-트리히드록시아세토페논 일수화물을 수득하였다.Add 34 mL of ethanol to the intermediate product and stir for about 60 mL.

It was dissolved by raising the temperature to . Afterwards, 120 mL of purified water was slowly added and mixed for about 1 hour to prepare the final mixture. The final mixture was about 0~5

By cooling, a recrystallized product was obtained. Afterwards, the recrystallized product was filtered and washed with purified water. Afterwards, the process of adding ethanol and filtering the recrystallized product was repeated twice, and then dried to obtain 2', 4', 6'-trihydroxyacetophenone monohydrate.

Comparative Example 1

2', 4', 6'-trihydroxyacetophenone monohydrate was prepared in the same process as Example 1, except that the acetyl chloride included in the second reactant was changed to acetic anhydride.

Comparative Example 2

Except that the amount of acetyl chloride added was adjusted so that the molar ratio of benzene-1,3,5-triol (phloroglucinol) contained in the first reactant and acetyl chloride contained in the second reactant was 1:0.5, 2', 4', 6'-trihydroxyacetophenone monohydrate was prepared in the same process as Example 1.

Comparative Example 3

Except that the amount of acetyl chloride added was adjusted so that the molar ratio of benzene-1,3,5-triol (phloroglucinol) contained in the first reactant and acetyl chloride contained in the second reactant was 1:2, 2', 4', 6'-trihydroxyacetophenone monohydrate was prepared in the same process as Example 1.

Comparative Example 4

로 1시간동안 가열하였다. 반응혼합물을 상온으로 냉각하여 생성된 침전물을 여과하였다. 여액을 10% 탄산수소나트륨용액 100mL로 반응을 종결시킨 후 생성된 침전물을 여과하고 디에틸 에테르 300mL로 추출하였다. 여액에 무수황산나트륨을 투입하여 탈수처리하였다. 여액을 농축한 후 에탄올 24mL를 투입하고 60

로 승온하여 용해시키고 정제수 84mL를 천천히 투입하여 결정화시켰다. 혼합물을 0~5

냉각하여 생성된 결정을 여과하고 정제수 20mL로 세척하였다. 에탄올과 정제수로 재결정을 2차례 실시하고 건조하여 2', 4', 6'-트리히드록시아세토페논 일수화물을 얻었다.50 mL (872 mmol) of glacial acetic acid was added to 20 g (158 mmol) of benzene-1, 3, 5-triol (phloroglucinol) and stirred under nitrogen conditions. Add 20mL (158mmol) of boron trifluoride diethyl ether and mix to 85±5.

It was heated for 1 hour. The reaction mixture was cooled to room temperature, and the resulting precipitate was filtered. The reaction was terminated with 100 mL of 10% sodium bicarbonate solution, and the resulting precipitate was filtered and extracted with 300 mL of diethyl ether. The filtrate was dehydrated by adding anhydrous sodium sulfate. After concentrating the filtrate, 24 mL of ethanol was added and 60 mL

The temperature was raised to dissolve, and 84 mL of purified water was slowly added to crystallize. Mixture 0~5

The crystals produced by cooling were filtered and washed with 20 mL of purified water. Recrystallization was performed twice with ethanol and purified water and dried to obtain 2', 4', 6'-trihydroxyacetophenone monohydrate.

Experiment result

The yield and purity of 2', 4', 6'-trihydroxyacetophenone monohydrate prepared in Example 1 and Comparative Examples 1 to 4 were measured and summarized in Table 1 below.

Example 1 Comparative Example 1 Comparative example 2 Comparative example 3 Comparative Example 4 water 99.8% 97.2% 99.0% 99.3% 99.5% transference number* 80% 48% 61% 73% 65% Yield* = (2', 4', 6'-trihydroxyacetophenone monohydrate/theoretical yield*) Х 100%
Theoretical yield* = 29.52g = Input amount of benzene-1,3,5-triol (phloroglucinol) (20g)/126.11g/mol (benzene-1,3,5-triol molecular weight)*186.16g /mol (2',4',6'-trihydroxyacetophenone molecular weight)

Looking at the results of the above comparative examples, it can be seen that the overall production yield is lower than that of the Example, and the purity of the prepared 2', 4', 6'-trihydroxyacetophenone monohydrate is relatively lower than that of the Example. You can see that it came out low. In conclusion, it can be expected that the relatively low purity 2', 4', 6'-trihydroxyacetophenone monohydrate of Comparative Examples 1 and 4 is not suitable for cholesterol lowering purposes. In addition, it can be expected that the overall yield of all comparative examples is low, so manufacturing efficiency may be very poor.

Above, the present invention has been described in more detail through drawings and examples. However, since the configurations described in the drawings or examples described in this specification are only one embodiment of the present invention and do not represent the entire technical idea of the present invention, at the time of filing this application, various equivalents and It should be understood that variations may exist.

Claims (15)

Preparing a mixture by reacting a first reactant containing benzene-1,3,5-triol (phloroglucinol) with a second reactant containing an acylation material (S1);
Creating an aqueous layer-organic layer mixture by adding purified water to the mixture and stirring it (S2);
Separating the organic layer of the aqueous layer-organic layer mixture, washing and concentrating the organic layer to obtain a crystalline intermediate product (S3);
Mixing the intermediate product with an alcohol mixed solvent to prepare an alcohol mixture (S4);
Preparing a final mixture by adding and mixing purified water to the alcohol mixture (S5);
Obtaining a recrystallized product by recrystallizing the final mixture (S6); and
Washing and filtering the recrystallized product (S7); Including,
A method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate, characterized in that the acylation material in step (S1) is acetyl chloride.
According to paragraph 1,
In step (S1), the first reactant is 2', 4', 6'-trihydroxyacetophenone monohydrate containing benzene-1,3,5-triol (phloroglucinol) and a first organic solvent. Manufacturing method.
According to paragraph 2,
A method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate, wherein the first organic solvent includes any one of dichloromethane, acetonitrile, and acetic acid.
According to paragraph 1,
In step (S1), the second reactant is 2', 4', 6'-trihydroxyacetophenone monohydrate further comprising a second organic solvent containing any one of dichloromethane, acetonitrile, and acetic acid, and a catalyst. Manufacturing method.
According to paragraph 1,
A method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate in which the second reactant is added to the first reactant in step (S1) and then stirred for 10 to 60 minutes to prepare a mixture.
According to paragraph 1,
Method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate wherein the molar ratio of benzene-1,3,5-triol (phloroglucinol) and acylation material is 1:0.6 to 1:1.9. .
According to paragraph 4,
The catalyst is a method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate comprising any one of aluminum chloride and boron trifluoride diethyl ether.
According to paragraph 4,
The first organic solvent and the second organic solvent each include dichloromethane,
The catalyst includes aluminum chloride,
The acylation material is a method of producing 2', 4', 6'-trihydroxyacetophenone monohydrate containing acetyl chloride.
According to paragraph 1,
A method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate in step (S2), wherein the aqueous layer-organic layer mixture is produced by stirring at a temperature of 0 to 5 degrees.
According to paragraph 1,
In step (S2), the purified water is added in a state solidified as ice and stirred until the solidified purified water melts.
According to paragraph 1,
In step (S4), the intermediate product and the alcohol mixed solvent are mixed at a temperature of 50 to 70 degrees Celsius.
According to paragraph 1,
In step (S5), the volume ratio of the alcohol mixed solvent and purified water is 1:3 to 1:5. Method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate.
According to paragraph 1,
In step (S6), the final mixture is cooled to 0 to 5 degrees Celsius and recrystallized.
According to paragraph 1,
The steps (S4) to (S7) are sequentially repeated 2 to 4 times in the method for producing 2', 4', 6'-trihydroxyacetophenone monohydrate.
Manufactured by the manufacturing method of paragraph 1,
2', 4', 6'-trihydroxyacetophenone monohydrate, which is used for lowering cholesterol.